Targeting BCAA Catabolism to Treat Obesity-Associated Insulin Resistance
Targeting BCAA Catabolism to Treat Obesity-Associated Insulin Resistance
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瞄准 BCAA 分解代谢来治疗肥胖相关的胰岛素抵抗
DOI：
10.2337/db18-0927
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发表时间：
2019-09-01
期刊：
影响因子：
7.7
通讯作者：
Sun, Haipeng
中科院分区：
文献类型：
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作者：
Zhou, Meiyi;Shao, Jing;Sun, Haipeng
最近的研究表明，血浆支链氨基酸(BCAA)升高与胰岛素抵抗(IR)密切相关。然而，两者之间的因果关系以及支链氨基酸动态平衡中断是否可以作为糖尿病的治疗靶点，仍有待实验建立。在这项研究中，无偏整合通路分析在人类和小鼠群体中确定了肥胖相关IR和支链氨基酸分解代谢基因表达在通路水平上的独特遗传联系。在遗传性肥胖(ob/ob)小鼠中，限速支链α-酮酸(BCKA)脱氢酶缺乏症(即BCAA和BCKA积聚)是一种代谢特征，伴随着BCAA分解代谢基因的系统性抑制。用BCKA脱氢酶抑制剂(BCKDK)恢复BCAA分解代谢通量，可降低肥胖小鼠BCAA和BCKA的丰度，显著降低IR。减少蛋白质摄入量(从而减少支链氨基酸)可获得类似的结果，而增加支链氨基酸摄入量则相反；这证实了支链氨基酸和支链氨基酸在肥胖/肥胖小鼠胰岛素抵抗中的致病作用。与BCAA一样，BCKA也通过激活哺乳动物靶标雷帕霉素复合体1来抑制胰岛素信号。最后，小分子BCKDK抑制剂显著减轻高脂饮食诱导的肥胖小鼠的IR。总之，这些数据证明了支链氨基酸分解代谢缺陷以及支链氨基酸和支链氨基酸丰度增加在肥胖相关胰岛素抵抗中的关键原因，并为操纵支链氨基酸代谢治疗糖尿病的治疗有效性提供了概念验证证据。
Recent studies implicate a strong association between elevated plasma branched-chain amino acids (BCAAs) and insulin resistance (IR). However, a causal relationship and whether interrupted BCAA homeostasis can serve as a therapeutic target for diabetes remain to be established experimentally. In this study, unbiased integrative pathway analyses identified a unique genetic link between obesity-associated IR and BCAA catabolic gene expression at the pathway level in human and mouse populations. In genetically obese (ob/ob) mice, rate-limiting branched-chain α-keto acid (BCKA) dehydrogenase deficiency (i.e., BCAA and BCKA accumulation), a metabolic feature, accompanied the systemic suppression of BCAA catabolic genes. Restoring BCAA catabolic flux with a pharmacological inhibitor of BCKA dehydrogenase kinase (BCKDK) ( a suppressor of BCKA dehydrogenase) reduced the abundance of BCAA and BCKA and markedly attenuated IR in ob/ob mice. Similar outcomes were achieved by reducing protein (and thus BCAA) intake, whereas increasing BCAA intake did the opposite; this corroborates the pathogenic roles of BCAAs and BCKAs in IR in ob/ob mice. Like BCAAs, BCKAs also suppressed insulin signaling via activation of mammalian target of rapamycin complex 1. Finally, the small-molecule BCKDK inhibitor significantly attenuated IR in high-fat diet–induced obese mice. Collectively, these data demonstrate a pivotal causal role of a BCAA catabolic defect and elevated abundance of BCAAs and BCKAs in obesity-associated IR and provide proof-of-concept evidence for the therapeutic validity of manipulating BCAA metabolism for treating diabetes.